EP1233962B1 - Composes heterocycliques et leur application a titre de medicaments - Google Patents
Composes heterocycliques et leur application a titre de medicaments Download PDFInfo
- Publication number
- EP1233962B1 EP1233962B1 EP00974646A EP00974646A EP1233962B1 EP 1233962 B1 EP1233962 B1 EP 1233962B1 EP 00974646 A EP00974646 A EP 00974646A EP 00974646 A EP00974646 A EP 00974646A EP 1233962 B1 EP1233962 B1 EP 1233962B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- amino
- radical
- hydrogen atom
- furanyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003814 drug Substances 0.000 title claims description 14
- 229940079593 drug Drugs 0.000 title description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 title 1
- -1 heterocyclylalkyl secondary amines Chemical class 0.000 claims abstract description 151
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 98
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 55
- 125000003118 aryl group Chemical group 0.000 claims abstract description 51
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 29
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 15
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims abstract description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 claims abstract 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 107
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 230000007170 pathology Effects 0.000 claims description 15
- LHPCGJVWVCFFAG-WSJPMQGYSA-N n-[(2s)-1-[[(3s)-2-hydroxyoxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]-10h-phenothiazine-2-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N[C@H]1CCOC1O LHPCGJVWVCFFAG-WSJPMQGYSA-N 0.000 claims description 11
- DCMUJUQQBAFVLJ-UHFFFAOYSA-N oxolan-2-yl acetate Chemical compound CC(=O)OC1CCCO1 DCMUJUQQBAFVLJ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 9
- 239000011707 mineral Substances 0.000 claims description 9
- OJYMQBJTUWINCQ-VEXWJQHLSA-N n-[4-[[(3s)-2-hydroxyoxolan-3-yl]carbamoyl]phenyl]-10h-phenothiazine-2-carboxamide Chemical compound OC1OCC[C@@H]1NC(=O)C(C=C1)=CC=C1NC(=O)C1=CC=C(SC=2C(=CC=CC=2)N2)C2=C1 OJYMQBJTUWINCQ-VEXWJQHLSA-N 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 235000005985 organic acids Nutrition 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- NJTHYOLHELBCME-SZQRVLIRSA-N n-[(3s)-2-hydroxyoxolan-3-yl]-2-(10h-phenothiazin-2-yl)-1,3-thiazole-4-carboxamide Chemical compound OC1OCC[C@@H]1NC(=O)C1=CSC(C=2C=C3NC4=CC=CC=C4SC3=CC=2)=N1 NJTHYOLHELBCME-SZQRVLIRSA-N 0.000 claims description 6
- IULASNWSNYIFLZ-UHFFFAOYSA-N 2-(10h-phenothiazin-2-yl)-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC(C=2C=C3NC4=CC=CC=C4SC3=CC=2)=N1 IULASNWSNYIFLZ-UHFFFAOYSA-N 0.000 claims description 5
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229940049953 phenylacetate Drugs 0.000 claims description 5
- 230000003612 virological effect Effects 0.000 claims description 5
- YZPGMLLZUAPPGY-HNNXBMFYSA-N (2s)-4-methyl-2-(10h-phenothiazine-2-carbonylamino)pentanoic acid Chemical compound C1=CC=C2NC3=CC(C(=O)N[C@@H](CC(C)C)C(O)=O)=CC=C3SC2=C1 YZPGMLLZUAPPGY-HNNXBMFYSA-N 0.000 claims description 4
- WGKXSFJXMGAPSW-UHFFFAOYSA-N 4-(10h-phenothiazine-2-carbonylamino)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC(=O)C1=CC=C(SC=2C(=CC=CC=2)N2)C2=C1 WGKXSFJXMGAPSW-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 230000001363 autoimmune Effects 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- MCRUVGPFTZPESY-UYHNVOLQSA-N n-[(2s)-1-[[(3s)-2-hydroxyoxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]-10h-phenothiazine-1-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=2NC3=CC=CC=C3SC=2C=CC=1)CC(C)C)N[C@H]1CCOC1O MCRUVGPFTZPESY-UYHNVOLQSA-N 0.000 claims description 4
- OJBNUTNJIVXJFM-WMZOPIPTSA-N n-[(2s)-4-methyl-1-oxo-1-[[(3s)-2-oxooxolan-3-yl]amino]pentan-2-yl]-10h-phenothiazine-2-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N[C@H]1CCOC1=O OJBNUTNJIVXJFM-WMZOPIPTSA-N 0.000 claims description 4
- WXLVUZGELHUMDN-ZDUSSCGKSA-N n-[(3s)-2-oxooxolan-3-yl]-2-(10h-phenothiazin-2-yl)-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C=2C=C3NC4=CC=CC=C4SC3=CC=2)=NC=1C(=O)N[C@H]1CCOC1=O WXLVUZGELHUMDN-ZDUSSCGKSA-N 0.000 claims description 4
- GRWXISMNHPYCGH-SFHVURJKSA-N n-[4-[[(3s)-2-oxooxolan-3-yl]carbamoyl]phenyl]-10h-phenothiazine-2-carboxamide Chemical compound C=1C=C(NC(=O)C=2C=C3NC4=CC=CC=C4SC3=CC=2)C=CC=1C(=O)N[C@H]1CCOC1=O GRWXISMNHPYCGH-SFHVURJKSA-N 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- NSASCSZNOMCMJP-FDDCHVKYSA-N (2r)-6-hydroxy-2,5,7,8-tetramethyl-n-[(2s)-1-oxo-3-phenylpropan-2-yl]-3,4-dihydrochromene-2-carboxamide Chemical compound C([C@H](NC(=O)[C@]1(C)OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C=O)C1=CC=CC=C1 NSASCSZNOMCMJP-FDDCHVKYSA-N 0.000 claims description 3
- YXCBEVMBMRSFNK-AWEZNQCLSA-N (2s)-4-methyl-2-(10h-phenothiazine-1-carbonylamino)pentanoic acid Chemical compound S1C2=CC=CC=C2NC2=C1C=CC=C2C(=O)N[C@@H](CC(C)C)C(O)=O YXCBEVMBMRSFNK-AWEZNQCLSA-N 0.000 claims description 3
- LWYMLUASRRBRGT-UHFFFAOYSA-N 1-propyl-2,3-dihydroindol-5-amine Chemical compound NC1=CC=C2N(CCC)CCC2=C1 LWYMLUASRRBRGT-UHFFFAOYSA-N 0.000 claims description 3
- RVRSAKGBTHIDDE-UHFFFAOYSA-N 3-(4-anilinoanilino)oxolan-2-one Chemical compound O=C1OCCC1NC(C=C1)=CC=C1NC1=CC=CC=C1 RVRSAKGBTHIDDE-UHFFFAOYSA-N 0.000 claims description 3
- VRTXYKSVMLSIHK-UHFFFAOYSA-N 3-oxo-2-phenyl-3-[(1-propyl-2,3-dihydroindol-5-yl)amino]propanoic acid Chemical compound C=1C=C2N(CCC)CCC2=CC=1NC(=O)C(C(O)=O)C1=CC=CC=C1 VRTXYKSVMLSIHK-UHFFFAOYSA-N 0.000 claims description 3
- QJBYQCKFQWLENS-UHFFFAOYSA-N 5-nitro-1-propyl-2,3-dihydroindole Chemical compound [O-][N+](=O)C1=CC=C2N(CCC)CCC2=C1 QJBYQCKFQWLENS-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000002177 Cataract Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- XYQKVJRQVSZINV-UHFFFAOYSA-N benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate Chemical compound C=1C=CC=CC=1COC(=O)C(C=1C=CC=CC=1)C(=O)NC(C=C1)=CC=C1NC1=CC=CC=C1 XYQKVJRQVSZINV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 201000006938 muscular dystrophy Diseases 0.000 claims description 3
- UGIRJZOABQQFTB-IRXDYDNUSA-N n-[(2s)-4-methyl-1-oxo-1-[[(3s)-2-oxooxolan-3-yl]amino]pentan-2-yl]-10h-phenothiazine-1-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=2NC3=CC=CC=C3SC=2C=CC=1)CC(C)C)N[C@H]1CCOC1=O UGIRJZOABQQFTB-IRXDYDNUSA-N 0.000 claims description 3
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- LKTLNHROECVUDB-HNNXBMFYSA-N 1-(2-anilinophenyl)-3-[(3s)-2-oxooxolan-3-yl]urea Chemical compound C=1C=CC=C(NC=2C=CC=CC=2)C=1NC(=O)N[C@H]1CCOC1=O LKTLNHROECVUDB-HNNXBMFYSA-N 0.000 claims description 2
- HJBVPXJSMQGQLO-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]-2,3-dihydroindole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2N(C(=O)OC(C)(C)C)CCC2=C1 HJBVPXJSMQGQLO-UHFFFAOYSA-N 0.000 claims description 2
- KANVSPBCQYQXFC-UHFFFAOYSA-N 1-o-tert-butyl 5-o-methyl 2,3-dihydroindole-1,5-dicarboxylate Chemical compound COC(=O)C1=CC=C2N(C(=O)OC(C)(C)C)CCC2=C1 KANVSPBCQYQXFC-UHFFFAOYSA-N 0.000 claims description 2
- QMAFIIQGPRDVII-UHFFFAOYSA-N 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C(=O)NC(C=C1)=CC=C1NC1=CC=CC=C1 QMAFIIQGPRDVII-UHFFFAOYSA-N 0.000 claims description 2
- KUQOIPMSCCZMQO-UHFFFAOYSA-N ethyl 2-(10h-phenothiazin-2-yl)-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(C=2C=C3NC4=CC=CC=C4SC3=CC=2)=N1 KUQOIPMSCCZMQO-UHFFFAOYSA-N 0.000 claims description 2
- WEMOAVIAIWJRIF-INIZCTEOSA-N methyl (2s)-4-methyl-2-(10h-phenothiazine-2-carbonylamino)pentanoate Chemical compound C1=CC=C2NC3=CC(C(=O)N[C@@H](CC(C)C)C(=O)OC)=CC=C3SC2=C1 WEMOAVIAIWJRIF-INIZCTEOSA-N 0.000 claims description 2
- HLEDIOBGKDPDSV-ZQRQZVKFSA-N n-[(3s)-2-oxooxolan-3-yl]-2-phenyl-n'-(1-propyl-2,3-dihydroindol-5-yl)propanediamide Chemical compound C=1C=C2N(CCC)CCC2=CC=1NC(=O)C(C=1C=CC=CC=1)C(=O)N[C@H]1CCOC1=O HLEDIOBGKDPDSV-ZQRQZVKFSA-N 0.000 claims description 2
- ODOZWPJRNQJKJQ-UHFFFAOYSA-N oxolan-2-yl morpholine-4-carboxylate Chemical compound N1(CCOCC1)C(=O)OC1OCCC1 ODOZWPJRNQJKJQ-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- OJKXMNJUDNZCQV-GOADRSPRSA-N [(3s)-3-[[(2s)-4-methyl-2-(10h-phenothiazine-2-carbonylamino)pentanoyl]amino]oxolan-2-yl] 2,2-dimethylpropanoate Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N[C@H]1CCOC1OC(=O)C(C)(C)C OJKXMNJUDNZCQV-GOADRSPRSA-N 0.000 claims 2
- YTCWZQOLIWKUPG-KHROREGQSA-N [(3s)-3-[[(2s)-4-methyl-2-(10h-phenothiazine-2-carbonylamino)pentanoyl]amino]oxolan-2-yl] acetate Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N[C@H]1CCOC1OC(C)=O YTCWZQOLIWKUPG-KHROREGQSA-N 0.000 claims 2
- XFQAMJSAJYRGBW-KRWDZBQOSA-N 1-[(2S)-1-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-4-methyl-1-oxopentan-2-yl]-10H-phenothiazine-2-carboxamide Chemical compound O1CCOC11CN(CC1)C(=O)[C@@H](CC(C)C)C1=C(C=CC=2SC3=CC=CC=C3NC1=2)C(=O)N XFQAMJSAJYRGBW-KRWDZBQOSA-N 0.000 claims 1
- 241001024304 Mino Species 0.000 claims 1
- OOFUGTYVCNWUNJ-MUEJSNBNSA-N [(3s)-3-[[(2s)-4-methyl-2-(10h-phenothiazine-2-carbonylamino)pentanoyl]amino]oxolan-2-yl] 3,3-dimethylbutanoate Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N[C@H]1CCOC1OC(=O)CC(C)(C)C OOFUGTYVCNWUNJ-MUEJSNBNSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- ITDXRQNJLBDMIT-YADARESESA-N methyl (2s)-2-[[(2r)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carbonyl]amino]-3-phenylpropanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@]1(C)OC2=C(C)C(C)=C(O)C(C)=C2CC1)C1=CC=CC=C1 ITDXRQNJLBDMIT-YADARESESA-N 0.000 claims 1
- AREDUDVDDMCGKH-FQEVSTJZSA-N methyl (2s)-2-[[4-(4-anilinoanilino)-4-oxobutanoyl]amino]-4-methylpentanoate Chemical compound C1=CC(NC(=O)CCC(=O)N[C@@H](CC(C)C)C(=O)OC)=CC=C1NC1=CC=CC=C1 AREDUDVDDMCGKH-FQEVSTJZSA-N 0.000 claims 1
- JGHAHDCNUDPDID-HNNXBMFYSA-N methyl (2s)-4-methyl-2-(10h-phenothiazine-1-carbonylamino)pentanoate Chemical compound S1C2=CC=CC=C2NC2=C1C=CC=C2C(=O)N[C@@H](CC(C)C)C(=O)OC JGHAHDCNUDPDID-HNNXBMFYSA-N 0.000 claims 1
- OIHMTFPUTVLPKE-UHFFFAOYSA-N methyl 4-(10h-phenothiazine-2-carbonylamino)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NC(=O)C1=CC=C(SC=2C(=CC=CC=2)N2)C2=C1 OIHMTFPUTVLPKE-UHFFFAOYSA-N 0.000 claims 1
- JKVZHZIYBZLQCZ-KNVGNIICSA-N tert-butyl 5-[[(3s)-2-hydroxyoxolan-3-yl]carbamoyl]-2,3-dihydroindole-1-carboxylate Chemical compound C=1C=C2N(C(=O)OC(C)(C)C)CCC2=CC=1C(=O)N[C@H]1CCOC1O JKVZHZIYBZLQCZ-KNVGNIICSA-N 0.000 claims 1
- SWTJHIBVVDBWGA-ZDUSSCGKSA-N tert-butyl 5-[[(3s)-2-oxooxolan-3-yl]carbamoyl]-2,3-dihydroindole-1-carboxylate Chemical compound C=1C=C2N(C(=O)OC(C)(C)C)CCC2=CC=1C(=O)N[C@H]1CCOC1=O SWTJHIBVVDBWGA-ZDUSSCGKSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 130
- 239000002253 acid Substances 0.000 abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 13
- 102000007590 Calpain Human genes 0.000 abstract description 10
- 108010032088 Calpain Proteins 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 abstract description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004429 atom Chemical group 0.000 abstract description 2
- 230000002000 scavenging effect Effects 0.000 abstract description 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 4
- 125000005907 alkyl ester group Chemical group 0.000 abstract 2
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- 230000005764 inhibitory process Effects 0.000 abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- 230000001966 cerebroprotective effect Effects 0.000 abstract 1
- 239000000824 cytostatic agent Substances 0.000 abstract 1
- 230000001085 cytostatic effect Effects 0.000 abstract 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 1
- 230000001506 immunosuppresive effect Effects 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 230000000926 neurological effect Effects 0.000 abstract 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 abstract 1
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract 1
- 239000012873 virucide Substances 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 description 37
- 239000000243 solution Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 17
- 150000001735 carboxylic acids Chemical class 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000009833 condensation Methods 0.000 description 11
- 230000005494 condensation Effects 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001448 anilines Chemical class 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000002596 lactones Chemical group 0.000 description 5
- 230000003859 lipid peroxidation Effects 0.000 description 5
- 229940118019 malondialdehyde Drugs 0.000 description 5
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 description 5
- 229950010765 pivalate Drugs 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 0 **(CC1**C(N(*)*)=O)COC1=O Chemical compound **(CC1**C(N(*)*)=O)COC1=O 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 235000013877 carbamide Nutrition 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 150000002828 nitro derivatives Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 150000003672 ureas Chemical class 0.000 description 3
- KYRUBEDJIZVJRO-IBGZPJMESA-N (2S)-2-[[4-(4-anilinoanilino)-4-oxobutanoyl]amino]-4-methylpentanoic acid Chemical compound C1=CC(NC(=O)CCC(=O)N[C@@H](CC(C)C)C(O)=O)=CC=C1NC1=CC=CC=C1 KYRUBEDJIZVJRO-IBGZPJMESA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VYOKOQDVBBWPKO-UHFFFAOYSA-N 1-nitro-9h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1C([N+](=O)[O-])=CC=C2 VYOKOQDVBBWPKO-UHFFFAOYSA-N 0.000 description 2
- CBFANMJNNUVDTB-UHFFFAOYSA-N 10h-phenothiazine-2-carboxylic acid Chemical compound C1=CC=C2NC3=CC(C(=O)O)=CC=C3SC2=C1 CBFANMJNNUVDTB-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 2
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- RIYLNECMTVNMSO-GOTSBHOMSA-N N-succinyl-Leu-Tyr-7-amido-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 RIYLNECMTVNMSO-GOTSBHOMSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 108010079785 calpain inhibitors Proteins 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- MXDFLSHEUBUOMS-FQEVSTJZSA-N n-[(2s)-1-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-4-methyl-1-oxopentan-2-yl]-10h-phenothiazine-2-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=C2NC3=CC=CC=C3SC2=CC=1)CC(C)C)N(C1)CCC21OCCO2 MXDFLSHEUBUOMS-FQEVSTJZSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 238000005502 peroxidation Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2r,3s,4s,5r)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- HOGIQTACRLIOHC-JTQLQIEISA-N (2s)-2-(dimethylazaniumyl)-3-phenylpropanoate Chemical compound CN(C)[C@H](C(O)=O)CC1=CC=CC=C1 HOGIQTACRLIOHC-JTQLQIEISA-N 0.000 description 1
- XYXYXSKSTZAEJW-VIFPVBQESA-N (2s)-2-(phenylmethoxycarbonylamino)butanedioic acid Chemical class OC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 XYXYXSKSTZAEJW-VIFPVBQESA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- YHYKLKNNBYLTQY-UHFFFAOYSA-N 1,1-diphenylhydrazine Chemical class C=1C=CC=CC=1N(N)C1=CC=CC=C1 YHYKLKNNBYLTQY-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- SFWZZSXCWQTORH-UHFFFAOYSA-N 1-methyl-2-phenylindole Chemical compound C=1C2=CC=CC=C2N(C)C=1C1=CC=CC=C1 SFWZZSXCWQTORH-UHFFFAOYSA-N 0.000 description 1
- ALTGNKHNQHUIKE-UHFFFAOYSA-N 1-nitro-10h-phenothiazine Chemical class S1C2=CC=CC=C2NC2=C1C=CC=C2[N+](=O)[O-] ALTGNKHNQHUIKE-UHFFFAOYSA-N 0.000 description 1
- AXHVNJGQOJFMHT-UHFFFAOYSA-N 1-tert-butyl-2-methylbenzene Chemical compound CC1=CC=CC=C1C(C)(C)C AXHVNJGQOJFMHT-UHFFFAOYSA-N 0.000 description 1
- XUKJDTCEYYOATE-UHFFFAOYSA-N 10h-phenothiazin-1-amine Chemical class S1C2=CC=CC=C2NC2=C1C=CC=C2N XUKJDTCEYYOATE-UHFFFAOYSA-N 0.000 description 1
- KMPDTDKCEBVAMG-UHFFFAOYSA-N 10h-phenothiazine-1-carboxylic acid Chemical compound S1C2=CC=CC=C2NC2=C1C=CC=C2C(=O)O KMPDTDKCEBVAMG-UHFFFAOYSA-N 0.000 description 1
- HEURGSITSQEMFD-UHFFFAOYSA-N 10h-phenothiazine-2-carbothioamide Chemical compound C1=CC=C2NC3=CC(C(=S)N)=CC=C3SC2=C1 HEURGSITSQEMFD-UHFFFAOYSA-N 0.000 description 1
- KETFITVSYVFHLU-UHFFFAOYSA-N 10h-phenothiazine-2-carboxamide Chemical compound C1=CC=C2NC3=CC(C(=O)N)=CC=C3SC2=C1 KETFITVSYVFHLU-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- RUKISNQKOIKZGT-UHFFFAOYSA-N 2-nitrodiphenylamine Chemical compound [O-][N+](=O)C1=CC=CC=C1NC1=CC=CC=C1 RUKISNQKOIKZGT-UHFFFAOYSA-N 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical class OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BUTKIHRNYUEGKB-UHFFFAOYSA-N 3,3-dimethylbutanoyl chloride Chemical compound CC(C)(C)CC(Cl)=O BUTKIHRNYUEGKB-UHFFFAOYSA-N 0.000 description 1
- AUUIARVPJHGTSA-UHFFFAOYSA-N 3-(aminomethyl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(CN)=CC2=C1 AUUIARVPJHGTSA-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- CLXYGCPNHLXLPD-UHFFFAOYSA-N 3-nitro-10h-phenothiazine Chemical compound C1=CC=C2SC3=CC([N+](=O)[O-])=CC=C3NC2=C1 CLXYGCPNHLXLPD-UHFFFAOYSA-N 0.000 description 1
- BROJDHDMRXJNGS-UHFFFAOYSA-N 4-(4-anilinoanilino)-4-oxobutanoic acid Chemical compound C1=CC(NC(=O)CCC(=O)O)=CC=C1NC1=CC=CC=C1 BROJDHDMRXJNGS-UHFFFAOYSA-N 0.000 description 1
- UCGWXXMEKDOFOB-NKUHCKNESA-N 5-[[(3S)-2-hydroxyoxolan-3-yl]carbamoyl]-2,3-dihydroindole-1-carboxylic acid Chemical compound OC1OCC[C@@H]1NC(=O)C1=CC=C(N(CC2)C(O)=O)C2=C1 UCGWXXMEKDOFOB-NKUHCKNESA-N 0.000 description 1
- BJKCMKLGTLFWGG-JTQLQIEISA-N 5-[[(3S)-2-oxooxolan-3-yl]carbamoyl]-2,3-dihydroindole-1-carboxylic acid Chemical compound C=1C=C2N(C(=O)O)CCC2=CC=1C(=O)N[C@H]1CCOC1=O BJKCMKLGTLFWGG-JTQLQIEISA-N 0.000 description 1
- ASVYHMUYLBMSKW-UHFFFAOYSA-N 6-nitro-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC([N+](=O)[O-])=CC=C21 ASVYHMUYLBMSKW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- YJKJAYFKPIUBAW-UHFFFAOYSA-N 9h-carbazol-1-amine Chemical class N1C2=CC=CC=C2C2=C1C(N)=CC=C2 YJKJAYFKPIUBAW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 102000004172 Cathepsin L Human genes 0.000 description 1
- 108090000624 Cathepsin L Proteins 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- KNFLIXBMSVKTJN-UHFFFAOYSA-N N'-(1-propyl-2,3-dihydroindol-5-yl)propanediamide Chemical compound C(CC(=O)N)(=O)NC=1C=C2CCN(C2=CC=1)CCC KNFLIXBMSVKTJN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 241001302210 Sida <water flea> Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001716 carbazoles Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- UNHHXUMBWVVHNX-UHFFFAOYSA-N carbonochloridic acid;morpholine Chemical compound OC(Cl)=O.C1COCCN1 UNHHXUMBWVVHNX-UHFFFAOYSA-N 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- PRAHCKGOTFKWKD-UHFFFAOYSA-N dimethyl(propyl)azanium;chloride Chemical compound Cl.CCCN(C)C PRAHCKGOTFKWKD-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- DODCBMODXGJOKD-RGMNGODLSA-N methyl (2s)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(C)C DODCBMODXGJOKD-RGMNGODLSA-N 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- IDSBYDWJBLIEOZ-FQEVSTJZSA-N n-(4-anilinophenyl)-n'-[(2s)-4-methyl-1-oxopentan-2-yl]butanediamide Chemical compound C1=CC(NC(=O)CCC(=O)N[C@@H](CC(C)C)C=O)=CC=C1NC1=CC=CC=C1 IDSBYDWJBLIEOZ-FQEVSTJZSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- RRMGHKAQGLHVOY-LSLKUGRBSA-N oxolan-2-yl (2S)-2-(dimethylamino)-3-phenylpropanoate Chemical compound CN(C)[C@@H](Cc1ccccc1)C(=O)OC1CCCO1 RRMGHKAQGLHVOY-LSLKUGRBSA-N 0.000 description 1
- UGKBTVICKIUXJF-UHFFFAOYSA-N oxolan-2-yl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1CCCO1 UGKBTVICKIUXJF-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000004986 phenylenediamines Chemical class 0.000 description 1
- 125000000109 phenylethoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel heterocyclic derivatives having calpain inhibitory activity and / or a reactive oxygen reactive activity (ROS).
- the invention also relates to their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as calpain inhibitors and scavengers of reactive forms of oxygen selectively or not.
- R 1 represents a hydrogen atom, a radical -OR 3 , -SR 3 , oxo or a cyclic acetal
- R 3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, wherein the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents selected from: alkyl, OH, alkoxy, nitro, cyano, halogen or -NR 4 R 5 ; R 4 and R 5 represent, independently, a hydrogen atom or an alkyl radical, or R 4 and R 5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R 2 represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl
- the compounds according to the present invention may comprise asymmetric carbon atoms (of configuration "R” or “S”). Accordingly, the present invention includes enantiomeric, diastereoisomeric forms and any combination of these forms, including racemic "RS" mixtures.
- RS racemic
- alkyl When alkyl is not given more precisely, it is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms such as, for example, the methyl, ethyl, propyl, isopropyl, butyl and isobutyl radicals. sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl.
- the alkoxy radicals may correspond to the alkyl radicals indicated above, such as, for example, methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy radicals.
- the alkylthio radicals may correspond to the alkyl radicals indicated above, for example methylthio or ethylthio.
- alkenyl when not more precise is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond).
- Halogen means fluorine, chlorine, bromine or iodine atoms.
- aryl is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being said heterocyclic when at least one of the rings which compose it comprises a heteroatom (O, N or S).
- An example of a carbocyclic aryl radical is phenyl or naphthyl.
- heterocyclic (or heteroaryl) aryl radical there may be mentioned thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.
- heterocycle or heterocycloalkyl
- Het or Z preferably represents a mono or bicyclic heterocycle, saturated or unsaturated, containing from 1 to 5 heteroatoms chosen from O, S, N.
- the atom Nitrogen may optionally be substituted with a radical selected from: alkyl, aryl, aralkyl and alkylcarbonyl.
- tetrahydrofuran tetrahydropyran
- oxetane oxepane
- tetrahydrothiophene tetrahydrothiopyran
- thietane pyrrolidine
- piperidine azetidine
- 1,3-dioxane 1,3-dioxolane
- 1,3-dithiolane 1,3-dithiolane
- pyrrolidine piperidine
- azetidine 1,3-dioxane
- 1,3-dioxolane 1,3-dithiolane
- 1 3-dithianne
- 1,3-oxathiolane 1,3-oxazolidine
- 1,3-imidazolidine 1,3-thiazolidine.
- an unsaturated heterocycle mention may be made of: thiophene, furan, pyrrole, imidazole, pyrazole, isothiazole, thiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, benzimidazole, benzofuran, benzopyran, 1,3-benzothiazole, benzoxazole, quinoline .
- Arylalkyl (or aralkyl) radicals denote the radicals in which the aryl and alkyl radicals respectively are as defined above, such as, for example, benzyl, phenethyl or naphthylmethyl.
- the aralkoxy (aryl-alkoxy) radicals denote the radicals in which the aryl and alkoxy radicals respectively are as defined above, such as, for example, benzyloxy or phenylethoxy.
- the arylalkylthio radicals denote the radicals in which the aryl and alkylthio radicals respectively are as defined above, such as, for example, benzylthio.
- alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl or aralkylcarbonyl radicals denote radicals in which the alkyl, heterocycloalkyl, aryl and aralkyl radicals respectively have the meaning indicated above.
- the heterocycle is preferably saturated and comprises from 4 to 7 members and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently selected from the group consisting of O, N and S.
- the said heterocycle may be, for example, the azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring.
- Said heterocycle may be substituted by one or more identical or different substituents selected from hydroxy, an alkyl, aryl, aralkyl or alkoxy radical or a halogen atom.
- the invention more particularly relates to compounds of formula (I) as defined above, wherein R 1 represents the hydrogen atom, the radical -OR 3 or oxo.
- the invention more particularly relates to compounds of formula (I) as defined above, in which X represents - (CH 2) n -, - (CH 2 ) n -CO-, -O- (CH 2 ) n -CO-, -CO-N (R 45 ) -D-CO-, -N (R 45 ) -CO- (CH 2 ) n -CO-, -N (R 45 ) -CO-C (R) 46 R 47) -CO-, -N (R 45) -CO-NH-C (R 46 R 47) -CO-, -N (R 45) - (CH 2) n -CO-, -CO-N (R 45 ) -C (R 46 R 47 ) -CO- or -Z-CO-, and preferentially when R 45 and R 47 represent the hydrogen atom, R 46 the hydrogen atom, an alkyl or phenyl radical, D the phenylene radical and Z the thiazole radical.
- the invention more particularly relates to compounds of formula (I) as defined above, wherein R 2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
- the invention more particularly relates to compounds of formula (I) as defined above, in which A represents A1 with W representing the sulfur atom, and preferably the radical of formula
- the compounds of formula I according to the invention can be prepared according to several synthetic routes according to the definition of variable groups.
- the compounds of general formula (I) in which Het represents the tetrahydrofuran ring and Y the radical - (CH 2 ) p may be prepared according to the following scheme: in which A, X, R 2 and R 3 are as described above, by condensation of the acids of general formula (II) with amines of general formula (III), under standard conditions of peptide synthesis (M. Bodanszky and A.
- Bodanszky The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984 )) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) (J. Med Chem (1992), 35 ( 23), 4464-4472) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) to lead to intermediate carboxamides of general formula (IV).
- DCC dicyclohexylcarbodiimide
- CDI 1,1'-carbonyldiimidazole
- EDC or WSCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
- the lactone ring of the intermediates of general formula (IV) is then reduced with the aid of a reducing agent such as, for example, diisobutylaluminum hydride (DIBAL), in an inert solvent such as, for example, THF or CH 2 Cl 2 , at a temperature ranging from 0 to -78 ° C.
- DIBAL diisobutylaluminum hydride
- the lactol derivative of general formula (I ') thus obtained can be acylated using, for example, an acid chloride (R 3 -Cl) or an acid anhydride (acetic anhydride, benzoyl chloride, etc.) in the presence of a base such as, for example, triethylamine, in an inert solvent such as for example CH 2 Cl 2 for lead to the compound of general formula (I).
- a base such as, for example, triethylamine
- the compounds of the present invention possess interesting pharmacological properties: they exhibit a calpain inhibitory activity and / or a scavenging activity of the reactive forms of oxygen.
- the compounds of the present invention can thus be used in various therapeutic applications. They can produce beneficial or favorable effects in the treatment of pathologies where these enzymes and / or these radical species are involved.
- the subject of the present application is also, as medicaments, the products of formula I as defined above, as well as the addition salts with inorganic or organic acids or the pharmaceutically acceptable inorganic and organic bases of said products of formula I, as well as pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above.
- the invention thus relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid additive salt thereof, in combination with a pharmaceutically acceptable carrier.
- the pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories.
- Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
- compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups.
- suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof, in varying proportions, in water, added to pharmaceutically acceptable oils or fats.
- Sterile liquid compositions may be used for intramuscular, intraperitoneal or subcutaneous injections and sterile compositions may also be administered intravenously.
- R a 1 represents a hydrogen atom, a radical -OR 3 , -SR 3 , oxo or a cyclic acetal, in which R 3 represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical, wherein the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents selected from: alkyl, OH, alkoxy, nitro, cyano, halogen or -NR 4 R 5 ; R 4 and R 5 represent, independently, a hydrogen atom or an alkyl radical, or R 4 and R 5 together with the nitrogen atom to which they are attached form an
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above, for the preparation of medicaments for the treatment of pathologies where the reactive forms of oxygen are involved.
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above, for the preparation of medicaments for the treatment of pathologies where the reactive forms of oxygen and calpains are involved. .
- the invention therefore relates to the use of compounds of formula (I a) as defined above, for the preparation of medicaments for the treatment of pathologies such as inflammatory and immunological diseases, cardiovascular disease and cerebrovascular disease, disorders of the central or peripheral nervous system, osteoporosis, muscular dystrophies, proliferative diseases, cataracts, organ transplants, autoimmune and viral diseases, cancer, and all pathologies characterized by excessive production ROS and / or calpain activation.
- pathologies such as inflammatory and immunological diseases, cardiovascular disease and cerebrovascular disease, disorders of the central or peripheral nervous system, osteoporosis, muscular dystrophies, proliferative diseases, cataracts, organ transplants, autoimmune and viral diseases, cancer, and all pathologies characterized by excessive production ROS and / or calpain activation.
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above, characterized in that R 1 represents the hydrogen atom, the radical -OR 3 or oxo.
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above, characterized in that X represents - (CH 2 ) n -, - (CH 2 ) n -CO-, -O- (CH 2 ) n -CO-, -CO-N (R 45 ) -D-CO-, -Z-CO-, -N (R 45 ) -CO- (CH 2 ) n -CO-, -N (R 45) -CO-C (R 46 R 47) -CO-, -N (R 45) - (CH 2) n -CO-, -N (R 45) -CO-NH-C (R 46 R 47 ) -CO- or -CO-N (R 45 ) -C (R 46 R 47 ) -CO and preferentially when R 45 and R 47 represent the hydrogen atom, R 46 the hydrogen atom, an alkyl or phenyl radical, D is the phenylene radical and
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above characterized in that R 2 represents a hydrogen atom or an aralkyl radical, and preferably the benzyl radical.
- the invention more particularly relates to the use of compounds of formula (I a ) as defined above characterized in that A represents A1 with W representing the sulfur atom.
- A represents the radical
- the preparation of the carboxylic acids of general formula (II) can be carried out, in this case, from 3 different acid-ester derivatives (II.2), (II.A) and (II.6):
- the synthesis of the carboxylic acids of general formula (II) can also be carried out by condensation of the anilines of general formula (II.1) with the acid-ester derivatives of general formula (II.4) under the conditions previously described. This condensation is followed by a conventional saponification to yield acids of general formula (II).
- the synthesis of intermediates of general formula (II.4) is described below.
- carboxylic acids of general formula (II) are also accessible by the opening of cyclic anhydrides such as, for example, anhydride.
- succinic using amines of general formula (II.1) according to an experimental protocol described in the literature (J. Amer Chem Soc. (1951) 73, 4007).
- Anilines of general formula (II.1) non-commercial, derived from indoline or 1,2,3,4-tetrahydroquinoline, scheme 1.1.1, in which T and R 38 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (II.1.1). 6-Nitro-1,2,3,4-tetrahydroquinoline is described in Can. J. Chem. (1952), 30, 720-722.
- Alkylation of the amine is typically carried out by a strong base such as, e.g., NaH, in a polar aprotic solvent such as, for example, DMF in the presence of a halogenated derivative R 38 -Hal, such as by for example, 3-dimethylaminopropane chloride or benzyl bromide.
- a strong base such as, e.g., NaH
- a polar aprotic solvent such as, for example, DMF
- a halogenated derivative R 38 -Hal such as by for example, 3-dimethylaminopropane chloride or benzyl bromide.
- R 38 -Hal such as by for example, 3-dimethylaminopropane chloride or benzyl bromide.
- the nitro derivative of general formula (II.1.2) intermediately obtained is then reduced, for example, by Raney nickel in the presence of hydrazine hydrate to yield the anilines of general formula (I
- the anilines of general formula (II.1) are obtained by hydrogenation, in the presence of Pd / C, precursor nitrophenol derivatives.
- the nitro derivatives of the di-alkyl phenols are accessible according to the methods described in J. Org. Chem. (1968) 33 (1), 223-226 or J. Med. Chem. (1998), 41, 1846-1854.
- A is a carbazole derivative (W then represents a direct bond)
- the methods for preparing the aminocarbazoles of general formula (II.1) go through the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48 (11), 817-820; Synth. Common. (1994) 24 (1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org. Chem. (1964) 29 (8), 2474-2476; Org. Prep. Procedé. Int. (1981) 13 (6), 419-421 or J. Org. Chem. (1963) 28, 884.
- the reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney nickel.
- the acid esters of general formula (II.4), scheme 1.1.2, can be prepared from commercial diesters of general formula (II.4.1) according to a method described in the literature (Tetrahedron Asymmetry (1997) 8 (11)). ), 1821-1823).
- the carboxylic acid intermediates of general formula (II) are also accessible from the condensation of the carboxylic acids of general formula (II.8) with commercial amino esters of general formula (II.9A) or (II.9B), Figure 1.2 during a peptide synthesis step previously described.
- the carboxamides obtained intermediately (II.10A) and (II.10B) are then saponified to yield carboxylic acids of general formula (II).
- the carboxylic derivatives of general formula (II.8) which are not commercially accessible, can be prepared from the literature (for example: J. Org Chem (1961) 26, 1221-1223, Acta Chem Scandinavica ( 1973) 27, 888-890, Can J. Chem (1972) 50, 1276-1282, J. Med Chem (1992) 35 (4), 716-724, J. Org Chem (1989). 54, 560-569, J. Med Chem (1998) 41 (2), 148-156, Bull Soc., Chim Fr. (1960), 1049-1066).
- the acids of general formula (II) (Scheme 1.3) in which X represents -O- (CH 2 ) n -CO-, are prepared from the hydroquinones of general formula (II.11) obtained according to the literature (J. Chem Perkin 1 (1981) 303-306).
- the condensation with commercial halogens of general formula (II.12) is carried out in the presence of a base such as, for example K 2 CO 3 , by heating in a polar solvent such as, for example, THF for at least 5 hours. .
- the esters of general formula (II.13) intermediately obtained are then deprotected (in an acid medium in the case of tert-butyl esters) to yield acids of general formula (II).
- the preparation of the aldehydes of general formula (II.17) is conventionally carried out after activation of the acid function of the intermediates of general formula (II.8) in ester or alkylhydroxamate form, in the presence of DIBAL or of LiAlH 4 , according to experimental protocols of the literature (eg, J. Med Chem (1990) 33, 11-13).
- the reaction of these aldehydes with cysteine in the presence of acetate salts leads directly to thiazolidines of general formula (II.18) according to an experimental protocol described in J. Org. Chem. (1957) 22, 943-946.
- the thiazolidine ring amine is then protected as carbamate (eg Boc) under standard literature conditions to yield the carboxylic acids of general formula (II).
- Example 17 N - [(1S) -1 - ( ⁇ [(3S) -2-Hydroxytetrahydro-3-furanyl] amino ⁇ carbonyl) -3-methylbutyl] -10H-phenothiazine-2-carboxamide:
- the organic phase is decanted and washed successively with 50 ml H 2 O, 50 ml of a saturated solution of N A HCO 3 and 50 ml of brine.
- the organic solution is dried over magnesium sulfate, filtered and concentrated to dryness under vacuum.
- the evaporation residue is taken up in Et 2 O and filtered. Yellow powder (71%). Melting point: 160.5-161 ° C.
- Example 18 Acetate of (3 S) -3 - ( ⁇ (2 S) -4-methyl-2 - [(10 H -phenothiazin-2-ylcarbonyl) -amino] pentanoyl ⁇ amino) tetrahydro-2-furanyl:
- the experimental protocol used is identical to that described for Compound 17, the acid 10 H phenothiazine-1-carboxylic acid replacing the 10 H phenothiazine-2-carboxylic acid. Yellow powder. Melting point: 99-101 ° C.
- Example 22 The experimental protocol used is the same as that described for Example 22, starting from intermediate 17.4 and morpholine chloroformate. Yellow solid. Melting point: 165-167 ° C.
- the IC 50 are determined by the calculation of fluorescence product / fluorescence DMSO control ratios.
- Composition of the enzyma reaction buffer tick 50 mM Tris-HCl pH 7.5, 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 5 mM b-Mercaptoethanol, 1 mM Suc-LY-AMC (Bachem, ref. 1-1355) and 2.5 U / ml Calpain I (porcine erythrocytes, Calbiochem ref 208712).
- the IC 50 value of certain compounds according to the invention is less than 5 .mu.M.
- the inhibitory activity of the products of the invention is determined by measuring their effects on the degree of lipid peroxidation, determined by the concentration of malondialdehyde (MDA).
- MDA malondialdehyde
- the pellet is stored at -80 ° C. On the day of the experiment, the pellet is resuspended at a concentration of 1 g / 15 ml and centrifuged at 515 g for 10 minutes at 4 ° C. The supernatant is used immediately for the determination of lipid peroxidation.
- the homogenate of rat cerebral cortex 500 ⁇ l is incubated at 37 ° C. for 15 minutes in the presence of the compounds to be tested or of the solvent (10 ⁇ l). The lipid peroxidation reaction is initiated by the addition of 50 ⁇ l of 1 mM FeCl 2, 1 mM EDTA and 4 mM ascorbic acid.
- the MDA is quantified by means of a colorimetric test, by reacting a color-forming reagent (R) with N-methyl-2-phenylindole (650 ⁇ l) with 200 ⁇ l of the homogenate for 1 hour at 45 ° C. Condensation of an MDA molecule with two molecules of reagent R produces a stable chromophore whose maximum absorbance wavelength is 586 nm. (Caldwell et al., European J. Pharmacol (1995) 285, 203-206). In this test, the IC 50 value of the compounds according to the invention is less than 5 ⁇ M .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- Vascular Medicine (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05077194A EP1661564A1 (fr) | 1999-11-05 | 2000-11-03 | Nouveaux composés hétérocycliques et leur application à titre de médicaments |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9913858 | 1999-11-05 | ||
FR9913858A FR2800737B1 (fr) | 1999-11-05 | 1999-11-05 | Nouveaux composes heterocycliques et leur application a titre de medicaments |
FR0006535A FR2809398B3 (fr) | 2000-05-23 | 2000-05-23 | Nouveaux composes heterocycliques et leur application a titre de medicaments |
FR0006535 | 2000-05-23 | ||
PCT/FR2000/003067 WO2001032654A2 (fr) | 1999-11-05 | 2000-11-03 | Nouveaux composes heterocycliques et leur application a titre de medicaments |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05077194A Division EP1661564A1 (fr) | 1999-11-05 | 2000-11-03 | Nouveaux composés hétérocycliques et leur application à titre de médicaments |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1233962A2 EP1233962A2 (fr) | 2002-08-28 |
EP1233962B1 true EP1233962B1 (fr) | 2006-03-01 |
Family
ID=26212416
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05077194A Withdrawn EP1661564A1 (fr) | 1999-11-05 | 2000-11-03 | Nouveaux composés hétérocycliques et leur application à titre de médicaments |
EP00974646A Expired - Lifetime EP1233962B1 (fr) | 1999-11-05 | 2000-11-03 | Composes heterocycliques et leur application a titre de medicaments |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05077194A Withdrawn EP1661564A1 (fr) | 1999-11-05 | 2000-11-03 | Nouveaux composés hétérocycliques et leur application à titre de médicaments |
Country Status (23)
Country | Link |
---|---|
US (2) | US6747024B1 (ru) |
EP (2) | EP1661564A1 (ru) |
JP (1) | JP2003513092A (ru) |
KR (1) | KR100725198B1 (ru) |
CN (1) | CN1317278C (ru) |
AT (1) | ATE318809T1 (ru) |
AU (2) | AU781551B2 (ru) |
BR (1) | BR0015315A (ru) |
CA (1) | CA2389685C (ru) |
CZ (1) | CZ20021548A3 (ru) |
DE (1) | DE60026348T2 (ru) |
ES (1) | ES2259617T3 (ru) |
HK (1) | HK1052706B (ru) |
HU (1) | HUP0203183A3 (ru) |
IL (2) | IL149177A0 (ru) |
IS (1) | IS2297B (ru) |
MX (1) | MXPA02004442A (ru) |
NO (1) | NO20022088L (ru) |
NZ (1) | NZ518420A (ru) |
PL (1) | PL200167B1 (ru) |
PT (1) | PT1233962E (ru) |
RU (1) | RU2260009C2 (ru) |
WO (1) | WO2001032654A2 (ru) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2816509B1 (fr) | 2000-11-15 | 2004-02-06 | Sod Conseils Rech Applic | Association d'inhibiteurs de calpaine et de piegeurs des formes reactives de l'oxygene |
GB0205175D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205165D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205166D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205162D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205176D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
GB0205170D0 (en) | 2002-03-06 | 2002-04-17 | Astrazeneca Ab | Chemical compounds |
TW200507841A (en) * | 2003-03-27 | 2005-03-01 | Glaxo Group Ltd | Antibacterial agents |
FR2863268B1 (fr) * | 2003-12-09 | 2006-02-24 | Sod Conseils Rech Applic | Nouveaux derives du 2-hydroxytetrahydrofuranne et leur application a titre de medicaments |
FR2867979B1 (fr) * | 2004-03-29 | 2006-06-30 | Sod Conseils Rech Applic | Nouvelle application therapeutique d'un derive de la phenothiazine |
ES2315868T3 (es) | 2004-03-29 | 2009-04-01 | Ipsen Pharma | Utilizacion de un derivado de la fenotiazina para la prevencion y/o el tratamiento de la perdida de audicion. |
EP1637529A1 (en) * | 2004-09-20 | 2006-03-22 | 4Sc Ag | Novel piperidin-4-yl-thiazole-carboxamide analogues as inhibitors of T-cell proliferation and uses thereof |
JP2008528604A (ja) * | 2005-01-25 | 2008-07-31 | グラクソ グループ リミテッド | 抗菌剤 |
EP1856126A2 (en) * | 2005-02-17 | 2007-11-21 | Wyeth a Corporation of the State of Delaware | Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives |
JP2009502816A (ja) * | 2005-07-29 | 2009-01-29 | 4エスツェー アクチェンゲゼルシャフト | 新規ヘテロ環状NF−κB阻害剤 |
FR2892415B1 (fr) * | 2005-10-21 | 2007-11-30 | Sod Conseils Rech Applic | Derives d'amidine et leurs applications a titre de medicament |
US7659266B2 (en) | 2005-10-21 | 2010-02-09 | S.C.R.A.S. | Amidine derivatives and their applications as a medicament |
FR2898357B1 (fr) * | 2006-03-07 | 2012-02-17 | Scras | Derives d'amidine et leurs applications a titre de medicament |
FR2898274B1 (fr) * | 2006-03-07 | 2008-10-03 | Sod Conseils Rech Applic | Composition contenant des derives d'amidine ou de carboxamide et des steroides a titre de medicament |
GB0614365D0 (en) * | 2006-07-19 | 2006-08-30 | Proaxon Ltd | Pharmaceutical compositions and their use |
BRPI0808737A2 (pt) * | 2007-03-15 | 2014-08-12 | Hoffmann La Roche | Malonamidas como antagonistas de orexinas. |
US7910622B2 (en) * | 2007-03-19 | 2011-03-22 | Wisconsin Alumni Research Foundation | Modulation of bacterial quorum sensing with synthetic ligands |
EP3251694A1 (en) | 2007-08-03 | 2017-12-06 | Summit (Oxford) Limited | Drug combinations for the treatment of duchenne muscular dystrophy |
GB0715087D0 (en) | 2007-08-03 | 2007-09-12 | Summit Corp Plc | Drug combinations for the treatment of duchenne muscular dystrophy |
EP3733642B1 (en) * | 2007-11-06 | 2024-05-08 | PTC Therapeutics, Inc. | 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
GB2467560A (en) * | 2009-02-06 | 2010-08-11 | Summit Corp Plc | Dual calpain-ROS inhibitors |
GB2467561A (en) * | 2009-02-06 | 2010-08-11 | Summit Corp Plc | Dual calpain-ROS inhibitors |
PT2427454E (pt) * | 2009-05-07 | 2013-06-20 | Envivo Pharmaceuticals Inc | Compostos fenoximetilo heterocíclicos |
US8624063B2 (en) | 2009-06-30 | 2014-01-07 | Wisconsin Alumni Research Foundation | Non-lactone carbocyclic and heterocyclic antagonists and agonists of bacterial quorum sensing |
US20140018402A1 (en) * | 2011-03-30 | 2014-01-16 | Catholic University Industry Academic Cooperation Foundation | Pharmaceutical composition for preventing or treating macular degeneration |
KR102254957B1 (ko) | 2013-11-22 | 2021-05-25 | 씨엘 바이오사이언시즈 엘엘씨 | 골다공증 치료 및 예방을 위한 가스트린 길항제(eg yf476, 네타제피드) |
US10882821B1 (en) | 2017-09-26 | 2021-01-05 | The Board Of Trustees Of The Leland Stanford Junior University | Enantiomeric compound for the reduction of the deleterious activity of extended nucleotide repeat containing genes |
US10526278B2 (en) | 2017-10-19 | 2020-01-07 | Wisconsin Alumni Research Foundation | Inhibitors of quorum sensing receptor LasR |
WO2021113627A1 (en) | 2019-12-06 | 2021-06-10 | Vertex Pharmaceuticals Incorporated | Substituted tetrahydrofurans as modulators of sodium channels |
JP2024522292A (ja) | 2021-06-04 | 2024-06-13 | バーテックス ファーマシューティカルズ インコーポレイテッド | ナトリウムチャネルのモジュレーターとしてのn-(ヒドロキシアルキル(ヘテロ)アリール)テトラヒドロフランカルボキサミド |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3634313A (en) * | 1967-05-18 | 1972-01-11 | American Cyanamid Co | Antiozonants for rubber |
FR2423476A1 (fr) * | 1978-04-06 | 1979-11-16 | Oreal | Nouvelles dihydroxy-2,4 diphenylamines et compositions tinctoriales pour cheveux les contenant |
JPS63130570A (ja) * | 1986-11-19 | 1988-06-02 | Yoshitomi Pharmaceut Ind Ltd | 3,5−ジ第3級ブチル−4−ヒドロキシ桂皮酸アミド誘導体 |
JPH03275657A (ja) * | 1989-07-05 | 1991-12-06 | Kanegafuchi Chem Ind Co Ltd | ケイ皮酸アミド誘導体 |
CA2111930A1 (en) * | 1992-12-25 | 1994-06-26 | Ryoichi Ando | Aminoketone derivatives |
NO943210L (no) | 1993-09-03 | 1995-03-06 | Takeda Chemical Industries Ltd | Laktolderivater, deres fremstilling og anvendelse |
US5691368A (en) | 1995-01-11 | 1997-11-25 | Hoechst Marion Roussel, Inc. | Substituted oxazolidine calpain and/or cathepsin B inhibitors |
WO1998001130A1 (fr) * | 1996-07-10 | 1998-01-15 | Mitsubishi Chemical Corporation | Agents de traitement des maladies ischemiques |
JPH10101558A (ja) * | 1996-07-10 | 1998-04-21 | Mitsubishi Chem Corp | 虚血性疾患治療薬 |
DE19650975A1 (de) | 1996-12-09 | 1998-06-10 | Basf Ag | Neue heterocyclisch substituierte Benzamide und deren Anwendung |
-
2000
- 2000-11-03 NZ NZ518420A patent/NZ518420A/en not_active IP Right Cessation
- 2000-11-03 JP JP2001534805A patent/JP2003513092A/ja active Pending
- 2000-11-03 PT PT00974646T patent/PT1233962E/pt unknown
- 2000-11-03 ES ES00974646T patent/ES2259617T3/es not_active Expired - Lifetime
- 2000-11-03 PL PL355286A patent/PL200167B1/pl not_active IP Right Cessation
- 2000-11-03 CZ CZ20021548A patent/CZ20021548A3/cs unknown
- 2000-11-03 WO PCT/FR2000/003067 patent/WO2001032654A2/fr active IP Right Grant
- 2000-11-03 MX MXPA02004442A patent/MXPA02004442A/es active IP Right Grant
- 2000-11-03 BR BR0015315-0A patent/BR0015315A/pt not_active Application Discontinuation
- 2000-11-03 KR KR1020027005798A patent/KR100725198B1/ko not_active IP Right Cessation
- 2000-11-03 DE DE60026348T patent/DE60026348T2/de not_active Expired - Lifetime
- 2000-11-03 HU HU0203183A patent/HUP0203183A3/hu unknown
- 2000-11-03 AU AU12871/01A patent/AU781551B2/en not_active Ceased
- 2000-11-03 RU RU2002114696/04A patent/RU2260009C2/ru not_active IP Right Cessation
- 2000-11-03 US US10/111,994 patent/US6747024B1/en not_active Expired - Fee Related
- 2000-11-03 AT AT00974646T patent/ATE318809T1/de active
- 2000-11-03 EP EP05077194A patent/EP1661564A1/fr not_active Withdrawn
- 2000-11-03 IL IL14917700A patent/IL149177A0/xx active IP Right Grant
- 2000-11-03 EP EP00974646A patent/EP1233962B1/fr not_active Expired - Lifetime
- 2000-11-03 CA CA2389685A patent/CA2389685C/fr not_active Expired - Fee Related
- 2000-11-03 CN CNB008159262A patent/CN1317278C/zh not_active Expired - Fee Related
-
2002
- 2002-04-16 IL IL149177A patent/IL149177A/en not_active IP Right Cessation
- 2002-05-02 NO NO20022088A patent/NO20022088L/no not_active Application Discontinuation
- 2002-05-03 IS IS6371A patent/IS2297B/is unknown
-
2003
- 2003-07-14 HK HK03105058.5A patent/HK1052706B/zh not_active IP Right Cessation
-
2004
- 2004-03-16 US US10/803,387 patent/US20040180936A1/en not_active Abandoned
-
2005
- 2005-08-18 AU AU2005203713A patent/AU2005203713A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1233962B1 (fr) | Composes heterocycliques et leur application a titre de medicaments | |
EP0557171A1 (fr) | Azaindoles, procédés de préparation et médicaments les contenant | |
FR2678938A1 (fr) | Derives de pyrrolidine, leur preparation et les medicaments les contenant. | |
EP1701974B1 (fr) | Nouveaux derives du 2-hydroxytetrahydrofuranne et leur application a titre de medicaments | |
EP0618193B1 (fr) | Dérivés bicycliques azotés, en tant qu'inhibiteurs de prolyl-endopeptidase | |
EP1954288B1 (fr) | Derives d'amidine et leurs applications a titre de medicament | |
EP0004494A1 (fr) | Nouveaux dérivés de 1,3-dihydro 3-(1-(2-(2,3-dihydro 1,4-benzo-dioxin-2-yl)2-hydroxy éthyl)pipéridin-4-yl)2H-indol 2-one, leur procédé de préparation, leur application comme médicaments et les compositions pharmaceutiques les renfermant | |
BE1001618A4 (fr) | Peptides et derives peptidiques, leur preparation et leur utilisation comme medicaments. | |
FR2809398A1 (fr) | Nouveaux composes heterocycliques et leur application a titre de medicaments | |
EP1993555B1 (fr) | Composition contenant des derives d'amidine ou de carboxamide et des steroides a titre de medicament | |
FR2800737A1 (fr) | Nouveaux composes heterocycliques et leur application a titre de medicaments | |
FR2822467A1 (fr) | Derives benzoxathiepines et leur utilisation comme medicaments | |
FR2892415A1 (fr) | Derives d'amidine et leurs applications a titre de medicament | |
FR2898357A1 (fr) | Derives d'amidine et leurs applications a titre de medicament | |
FR2619816A1 (fr) | Derives d'amine et leurs sels, leurs procedes de fabrication, et agent anti-ulcere les contenant | |
FR2554446A1 (fr) | Diamides derives d'azabicycloalcanes, leur preparation et compositions pharmaceutiques les contenant | |
FR2800069A1 (fr) | 3-amino-2,2-di-c-alkyl-1,4-butyrolactones et 1,4- thiobutyrolactones n-substituees utiles comme stimulant de l'activite de l'acide gamma-aminobutyrique et leur procede de preparation | |
WO2003095433A1 (fr) | Derives de l'acide hexahydro-pyridazine-3-carboxylique, compositions pharmaceutiques les contenant et leurs procedes de preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20020605 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Free format text: AL;LT;LV;MK;RO PAYMENT 20020605;SI |
|
17Q | First examination report despatched |
Effective date: 20031016 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Extension state: RO |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED. Effective date: 20060301 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20060301 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: LANGUAGE OF EP DOCUMENT: FRENCH |
|
REF | Corresponds to: |
Ref document number: 60026348 Country of ref document: DE Date of ref document: 20060427 Kind code of ref document: P |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20060601 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20060601 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: MICHELI & CIE INGENIEURS-CONSEILS |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20060401794 Country of ref document: GR |
|
GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) |
Effective date: 20060623 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Effective date: 20060531 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2259617 Country of ref document: ES Kind code of ref document: T3 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061130 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20061204 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20060301 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20060301 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: CA Ref country code: FR Ref legal event code: CD |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PCOW Free format text: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.);65 QUAI GEORGES GORSE;92100 BOULOGNE-BILLANCOURT (FR) Ref country code: CH Ref legal event code: PFA Owner name: IPSEN PHARMA S.A.S. Free format text: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.)#65 QUAI GEORGES GORSE#92100 BOULOGNE-BILLANCOURT (FR) -TRANSFER TO- IPSEN PHARMA S.A.S.#65 QUAI GEORGES GORSE#92100 BOULOGNE-BILLANCOURT (FR) |
|
NLT1 | Nl: modifications of names registered in virtue of documents presented to the patent office pursuant to art. 16 a, paragraph 1 |
Owner name: IPSEN PHARMA S.A.S. |
|
BECA | Be: change of holder's address |
Owner name: IPSEN PHARMA S.A.S.65 QUAI GEORGES GORSE, F-92100 Effective date: 20110207 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20121113 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20121031 Year of fee payment: 13 Ref country code: FR Payment date: 20121116 Year of fee payment: 13 Ref country code: CH Payment date: 20121113 Year of fee payment: 13 Ref country code: IE Payment date: 20121112 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20121113 Year of fee payment: 13 Ref country code: GB Payment date: 20121031 Year of fee payment: 13 Ref country code: GR Payment date: 20121016 Year of fee payment: 13 Ref country code: IT Payment date: 20121110 Year of fee payment: 13 Ref country code: ES Payment date: 20121212 Year of fee payment: 13 Ref country code: PT Payment date: 20120504 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20121110 Year of fee payment: 13 Ref country code: AT Payment date: 20121029 Year of fee payment: 13 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: MM4A Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 20140505 |
|
BERE | Be: lapsed |
Owner name: IPSEN PHARMA S.A.S. Effective date: 20131130 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: V1 Effective date: 20140601 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 318809 Country of ref document: AT Kind code of ref document: T Effective date: 20131103 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20131103 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131130 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131130 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: ML Ref document number: 20060401794 Country of ref document: GR Effective date: 20140603 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20140731 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 60026348 Country of ref document: DE Effective date: 20140603 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140603 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131103 Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140601 Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140603 Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140505 Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131103 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131130 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131103 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131202 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131103 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20150327 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131104 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20131103 |